Survey of Ophthalmology
Volume 48, Issue 3 , Pages 257-293 , May 2003

Age-Related Macular Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies

  • Jayakrishna Ambati, MD

      Affiliations

    • Ocular Angiogenesis Laboratory, Department of Ophthalmology, University of Kentucky, Lexington, KY USA
    • Massachusetts Eye&Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA USA
  • ,
  • Balamurali K Ambati, MD

      Affiliations

    • Massachusetts Eye&Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA USA
    • Department of Ophthalmology, Medical College of Georgia, Augusta, GA USA
  • ,
  • Sonia H Yoo, MD

      Affiliations

    • Massachusetts Eye&Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA USA
    • Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL USA
  • ,
  • Sean Ianchulev, MD

      Affiliations

    • Massachusetts Eye&Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA USA
  • ,
  • Anthony P Adamis, MD

      Affiliations

    • Massachusetts Eye&Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA USA
    • Children's Hospital, Harvard Medical School, Boston, MA USA
    • Eyetech Research Center, Woburn, MA, USA
    • Corresponding Author InformationReprint address: Anthony P. Adamis, MD, Eyetech Research and Development Center, 42 Cummings Park, Woburn, MA 01801. Dr. Adamis is an employee of Eyetech Pharmaceuticals

References 

  1. Abramson DH, Abramson HS. High-dose supplements for age-related macular degeneration: Did you leave out Centrum?. Arch Ophthalmol. 2002;120:1602
  2. Adachi Y, Itoh F, Yamamoto H, et al.  Matrix metalloproteinase matrilysin (MMP-7) participates in the progression of human gastric and esophageal cancers. Int J Oncol. 1998;13:1031–1035
  3. Adamis AP, Miller JW, Bernal MT, et al.  Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–450
  4. Adamis AP, Shima DT, Tolentino MJ, et al.  Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114:66–71
  5. Adamis AP, Shima DT, Yeo KT, et al.  Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun. 1993;193:631–638
  6. Age-Related Eye Disease Study Research Group . Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-related eye disease study report number 3. Ophthalmology. 2000;107:2224–2232
  7. Age-Related Eye Disease Study Research Group . A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417–1436
  8. Aiello LP, Pierce EA, Foley ED, et al.  Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA. 1995;92:10457–10461
  9. Aisenbrey S, Lafaut BA, Szurman P, et al.  Macular translocation with 360 degrees retinotomy for exudative age-related macular degeneration. Arch Ophthalmol. 2002;120:451–459
  10. Akduman L, Karavellas MP, MacDonald JC, Olk RJ, Freeman WR. Macular translocation with retinotomy and retinal rotation for exudative age-related macular degeneration. Retina. 1999;19:418–423
  11. Alder VA, Cringle SJ. The effect of the retinal circulation on vitreal oxygen tension. Curr Eye Res. 1985;4:121–129
  12. Algvere PV, Berglin L, Gouras P, Sheng Y. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with subfoveal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1994;232:707–716
  13. Algvere PV, Berglin L, Gouras P, Sheng Y, Kopp ED. Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol. 1997;235:149–158
  14. Allikmets R. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet. 2000;67:487–491
  15. Allikmets R, Seddon JM, Bernstein PS, et al.  Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies. Hum Genet. 1999;104:449–453
  16. Allikmets R, Shroyer NF, Singh N, et al.  Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997;277:1805–1807
  17. Allikmets R, Singh N, Sun H, et al.  A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236–246
  18. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med. 1995;1:1024–1028
  19. Alvarez A, Piqueras L, Blazquez MA, Sanz MJ. Cyclic AMP elevating agents and nitric oxide modulate angiotensin II-induced leukocyte-endothelial cell interactions in vivo. Br J Pharmacol. 2001;133:485–494
  20. Alvarez A, Sanz MJ. Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo. J Leukoc Biol. 2001;70:199–206
  21. Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci. 1998;39:18–22
  22. Ambati J, Adamis AP. Transscleral drug delivery to the retina and choroid. Prog Retin Eye Res. 2002;21:145–151
  23. Ambati J, Ambati BK. Age-related eye disease study caveats. Arch Ophthalmol. 2002;120:997–999
  24. Ambati J, Canakis CS, Miller JW, et al.  Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci. 2000;41:1181–1185
  25. Ambati J, Gragoudas ES, Miller JW, et al.  Transscleral delivery of bioactive protein to the choroid and retina. Invest Ophthalmol Vis Sci. 2000;41:1186–1191
  26. Amin R, Puklin JE, Frank RN. Growth factor localization in choroidal neovascular membranes of age-related macular degeneration. Invest Ophthalmol Vis Sci. 1994;35:3178–3188
  27. Anand-Apte B, Pepper MS, Voest E, et al.  Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci. 1997;38:817–823
  28. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411–431
  29. Anderson DH, Ozaki S, Nealon M, et al.  Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation. Am J Ophthalmol. 2001;131:767–781
  30. Ando A, Yang A, Mori K, et al.  Nitric oxide is proangiogenic in the retina and choroid. J Cell Physiol. 2002;191:116–124
  31. Applegate CA, Sunness JS, Guyer DR, et al.  A treatment trial for geographic atrophy from AMD: The GAARD Study. Invest Ophthalmol Vis Sci. 2001;42:S230
  32. Apte SS, Mattei MG, Olsen BR. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics. 1994;19:86–90
  33. Arnold JJ, Quaranta M, Soubrane G, Sarks SH, Coscas G. Indocyanine green angiography of drusen. Am J Ophthalmol. 1997;124:344–356
  34. Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen. A risk factor in age-related maculopathy. Retina. 1995;15:183–191
  35. Baffi J, Byrnes G, Chan CC, Csaky KG. Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 2000;41:3582–3589
  36. Baffi J, Byrnes G, Cousins SW, Csaky K. The recruitment of inflammatory cells into vascular endothelial growth factor (VEGF) induced choroidal neovascularization (CNV) in rat. Invest Ophthalmol Vis Sci. 2001;42:S227
  37. Ballinger SW, Van Houten B, Jin GF, Conklin CA, Godley BF. Hydrogen peroxide causes significant mitochondrial DNA damage in human RPE cells. Exp Eye Res. 1999;68:765–772
  38. Bazan HE, Bazan NG, Feeney-Burns L, Berman ER. Lipids in human lipofuscin-enriched subcellular fractions of two age populations. Comparison with rod outer segments and neural retina. Invest Ophthalmol Vis Sci. 1990;31:1433–1443
  39. Bazan NG. The metabolism of omega-3 polyunsaturated fatty acids in the eye: the possible role of docosahexaenoic acid and docosanoids in retinal physiology and ocular pathology. Prog Clin Biol Res. 1989;312:95–112
  40. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45:115–134
  41. Becerra SP, Palmer I, Kumar A, et al.  Overexpression of fetal human pigment epithelium-derived factor in Escherichia coli. A functionally active neurotrophic factor. J Biol Chem. 1993;268:23148–23156
  42. Becerra SP, Wu YQ, Montuenga L, Wong P, Pfeffer B. Pigment epithelium-derived factor (PEDF) in the monkey eye: apical secretion from the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2001;42:S772
  43. Becker MD, Kruse FE, Azzam L, Nobiling R, Reichling J, Volcker HE. In vivo significance of ICAM-1-dependent leukocyte adhesion in early corneal angiogenesis. Invest Ophthalmol Vis Sci. 1999;40:612–618
  44. Benner JD, Sunness JS, Ziegler MD, Soltanian J. Limited macular translocation for atrophic maculopathy. Arch Ophthalmol. 2002;120:586–591
  45. Berendschot TT, Willemse-Assink JJ, Bastiaanse M, et al.  Macular pigment and melanin in age-related maculopathy in a general population. Invest Ophthalmol Vis Sci. 2002;43:1928–1932
  46. Bergink GJ, Hoyng CB, van der Maazen RW, et al.  A randomized controlled clinical trial on the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in age-related macular degeneration: radiation versus observation. Graefes Arch Clin Exp Ophthalmol. 1998;236:321–325
  47. Berglin L, Sarman S, van der Ploeg I, et al.  Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice. Invest Ophthalmol Vis Sci. 2003;44:403–408
  48. Bermig J, Tylla H, Jochmann C, et al.  Angiographic findings in patients with exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2002;240:169–175
  49. Bernstein SL, Liu AM, Hansen BC, Somiari RI. Heat shock cognate-70 gene expression declines during normal aging of the primate retina. Invest Ophthalmol Vis Sci. 2000;41:2857–2862
  50. Bird AC, Marshall J. Retinal pigment epithelial detachments in the elderly. Trans Ophthalmol Soc UK. 1986;105:674–682
  51. Blaauwgeers HG, Holtkamp GM, Rutten H, et al.  Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol. 1999;155:421–428
  52. Blodi BA, AG3340 Study Group . Effects of prinomastat (AG3340), an angiogenesis inhibitor, in patients with subfoveal choroidal neovascularization associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;41:S311
  53. Blumenkranz MS, Russell SR, Robey MG, et al.  Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology. 1986;93:552–558
  54. Bok D. Retinal photoreceptor-pigment epithelium interactions. Friedenwald lecture. Invest Ophthalmol Vis Sci. 1985;26:1659–1694
  55. Boulton M, Moriarty P, Jarvis-Evans J, Marcyniuk B. Regional variation and age-related changes of lysosomal enzymes in the human retinal pigment epithelium. Br J Ophthalmol. 1994;78:125–129
  56. Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of choroidal neovascular membranes. Arch Ophthalmol. 1987;105:209–213
  57. Bressler NM, Munoz B, Maguire MG, et al.  Five-year incidence and disappearance of drusen and retinal pigment epithelial abnormalities. Waterman study. Arch Ophthalmol. 1995;113:301–308
  58. Bressler NM, Silva JC, Bressler SB, et al.  Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration. Retina. 1994;14:130–142
  59. Bressler SB, Maguire MG, Bressler NM, Fine SL. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Arch Ophthalmol. 1990;108:1442–1447
  60. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin αvβ3 for angiogenesis. Science. 1994;264:569–571
  61. Brooks SE, Gu X, Samuel S, et al.  Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice. Invest Ophthalmol Vis Sci. 2001;42:222–228
  62. Bush AI, Pettingell WH, Multhaup G, et al.  Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994;265:1464–1467
  63. Bush RA, Reme CE, Malnoe A. Light damage in the rat retina: the effect of dietary deprivation of N-3 fatty acids on acute structural alterations. Exp Eye Res. 1991;53:741–752
  64. Cai J, Wu M, Nelson KC, Sternberg P, Jones DP. Oxidant-induced apoptosis in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40:959–966
  65. Carmeliet P, Ferreira V, Breier G, et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439
  66. Carron JA, Hiscott P, Hagan S, et al.  Cultured human retinal pigment epithelial cells differentially express thrombospondin-1, -2, -3, and -4. Int J Biochem Cell Biol. 2000;32:1137–1142
  67. Casswell AG, Kohen D, Bird AC. Retinal pigment epithelial detachments in the elderly: classification and outcome. Br J Ophthalmol. 1985;69:397–403
  68. Char DH, Irvine AI, Posner MD, et al.  Randomized trial of radiation for age-related macular degeneration. Am J Ophthalmol. 1999;127:574–578
  69. Chen H, Wu L, Pan S, Wu DZ. An immunologic study on age-related macular degeneration. Yan Ke Xue Bao. 1993;9:113–120
  70. Chen JC, Fitzke FW, Pauleikhoff D, Bird AC. Functional loss in age-related Bruch's membrane change with choroidal perfusion defect. Invest Ophthalmol Vis Sci. 1992;33:334–340
  71. Cho E, Hankinson SE, Willett WC, et al.  Prospective study of alcohol consumption and the risk of age-related macular degeneration. Arch Ophthalmol. 2000;118:681–688
  72. Cho E, Hung S, Willett WC, et al.  Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001;73:209–218
  73. Cho E, Stampfer MJ, Seddon JM, et al.  Prospective study of zinc intake and the risk of age-related macular degeneration. Ann Epidemiol. 2001;11:328–336
  74. Choroidal Neovascularization Prevention Trial Research Group . Laser treatment in eyes with large drusen. Short-term effects seen in a pilot randomized clinical trial. Ophthalmology. 1998;105:11–23
  75. Christen WG, Glynn RJ, Ajani UA, et al.  Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol. 2001;119:1143–1149
  76. Christen WG, Glynn RJ, Manson JE, et al.  A prospective study of cigarette smoking and risk of age-related macular degeneration in men. J Am Med Assoc. 1996;276:1147–1151
  77. Chuang EL, Bird AC. The pathogenesis of tears of the retinal pigment epithelium. Am J Ophthalmol. 1988;105:285–290
  78. Cingle KA, Kalski RS, Bruner WE, et al.  Age-related changes of glycosidases in human retinal pigment epithelium. Curr Eye Res. 1996;15:433–438
  79. Ciulla TA, Criswell MH, Danis RP, Hill TE. Intravitreal triamcinolone acetonide inhibits choroidal neovascularization in a laser-treated rat model. Arch Ophthalmol. 2001;119:399–404
  80. Clauss M, Gerlach M, Gerlach H, et al.  Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990;172:1535–1545
  81. Cote J, Rosner B, Seddon JM: Smoking and AMD: results from a prospective study of men and women. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 4391, 2002
  82. Crabb JW, Miyagi M, Gu X, et al.  Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA. 2002;99:14682–14687
  83. Cruickshanks KJ, Klein R, Klein BE. Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Arch Ophthalmol. 1993;111:514–518
  84. Crum R, Szabo S, Folkman J. A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science. 1985;230:1375–1378
  85. Cunningham JJ, Fu A, Mearkle PL, Brown RG. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation. Metabolism. 1994;43:1558–1562
  86. Curcio CA, Millican CL. Basal linear deposit and large drusen are specific for early age-related maculopathy. Arch Ophthalmol. 1999;117:329–339
  87. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91:4082–4085
  88. Darzins P, Mitchell P, Heller RF. Sun exposure and age-related macular degeneration. An Australian case-control study. Ophthalmology. 1997;104:770–776
  89. Davies S, Elliott MH, Floor E, et al.  Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med. 2001;31:256–265
  90. Dawson DW, Volpert OV, Gillis P, et al.  Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285:245–248
  91. De La Paz M, Anderson RE. Region and age-dependent variation in susceptibility of the human retina to lipid peroxidation. Invest Ophthalmol Vis Sci. 1992;33:3497–3499
  92. De La Paz MA, Guy VK, Abou-Donia S, et al.  Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration. Ophthalmology. 1999;106:1531–1536
  93. De La Paz MA, Pericak-Vance MA, Lennon F, Haines JL, Seddon JM. Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1997;38:1060–1065
  94. Delcourt C, Diaz JL, Ponton-Sanchez A, Papoz L. Smoking and age-related macular degeneration. The POLA Study. Pathologies Oculaires Liees a l'Age. Arch Ophthalmol. 1998;116:1031–1035
  95. Delmelle M. Retinal sensitized photodynamic damage to liposomes. Photochem Photobiol. 1978;28:357–360
  96. Delori FC, Goger DG, Dorey CK. Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol Vis Sci. 2001;42:1855–1866
  97. Demetriades A-MM, Gehlbach PL, Yamamoto S, et al: Periocular injection of an adenoviral vector expressing the extracellular portion of vascular endothelial growth factor receptor-1 (Ads-flt.10) inhibits choroidal neovascularization. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 3916, 2002.
  98. Dithmar S, Curcio CA, Le NA, et al.  Ultrastructural changes in Bruch's membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci. 2000;41:2035–2042
  99. Dorey CK, Wu G, Ebenstein D, et al.  Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci. 1989;30:1691–1699
  100. Dulak J, Jozkowicz A, Dembinska-Kiec A, et al.  Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000;20:659–666
  101. Dunaief JL, Dentchev T, Ying G-S, Milam AH. The role of apoptosis in age-related macular degeneration. Arch Ophthalmol. 2002;120:1435–1442
  102. Duvall J, Tso MO. Cellular mechanisms of resolution of drusen after laser coagulation. An experimental study. Arch Ophthalmol. 1985;103:694–703
  103. Eckardt C, Eckardt U, Conrad HG. Macular rotation with and without counter-rotation of the globe in patients with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 1999;237:313–325
  104. Edelman JL, Castro MR. Quantitative image analysis of laser-induced choroidal neovascularization in rat. Exp Eye Res. 2000;71:523–533
  105. Edge R, McGarvey DJ, Truscott TG. The carotenoids as anti-oxidants-a review. J Photochem Photobiol B. 1997;41:189–200
  106. Eldred GE, Lasky MR. Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature. 1993;361:724–726
  107. Elman MJ, Fine SL, Murphy RP, et al.  The natural history of serous retinal pigment epithelium detachment in patients with age-related macular degeneration. Ophthalmology. 1986;93:224–230
  108. Espinosa-Heidmann DG, Suner I, Hernandez EP, et al.  Age as an independent risk factor for severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2002;43:1567–1573
  109. Evans J: Causes of blindness and partial sight in England and Wales. 1990–1991 London, Her's Majesty's Stationery Office, 1995
  110. Evans JR. Risk factors for age-related macular degeneration. Prog Retin Eye Res. 2001;20:227–253
  111. Eye Disease Case Control Study Group . Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol. 1993;111:104–109
  112. Fariss RN, Apte SS, Olsen BR, et al.  Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Am J Pathol. 1997;150:323–328
  113. Ferguson TA, Kaplan H, Tezel T, et al: Augmentation of choroidal neovascularization in a laser induced mouse model by PEDF. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 2756, 2002
  114. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–858
  115. Ferris FL, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102:1640–1642
  116. Figueroa MS, Regueras A, Bertrand J, et al.  Laser photo-coagulation for macular soft drusen. Updated results. Retina. 1997;17:378–384
  117. Finger PT, Chakravarthy U, Augsburger JJ. Radiotherapy and the treatment of age-related macular degeneration. External beam radiation therapy is effective in the treatment of age-related macular degeneration. Arch Ophthalmol. 1998;116:1507–1511
  118. Finnemann SC, Leung LW, Rodriguez-Boulan E. The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci USA. 2002;99:3842–3847
  119. Fisher RF. The influence of age on some ocular basement membranes. Eye. 1987;1:184–189
  120. Folk JC. Aging macular degeneration. Clinical features of treatable disease. Ophthalmology. 1985;92:594–602
  121. Fotsis T, Pepper M, Adlercreutz H, et al.  Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA. 1993;90:2690–2694
  122. Francois J, De Laey JJ, Cambie E, et al.  Neovascularization after argon laser photocoagulation of macular lesions. Am J Ophthalmol. 1975;79:206–210
  123. Frank HA. Structural determinations and spectroscopic studies of carotenoids reveal the factors important in controlling their function in biological systems. Eur J Clin Nutr. 1996;50(Suppl 3):S13–S16
  124. Frank RN, Amin RH, Eliott D, et al.  Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol. 1996;122:393–403
  125. Frennesson C, Nilsson UL, Nilsson SE. Colour contrast sensitivity in patients with soft drusen, an early stage of ARM. Doc Ophthalmol. 1995;90:377–386
  126. Frennesson IC, Nilsson SE. Laser photocoagulation of soft drusen in early age-related maculopathy (ARM). The one-year results of a prospective, randomised trial. Eur J Ophthalmol. 1996;6:307–314
  127. Freund KB, Yannuzzi LA, Sorenson JA. Age-related macular degeneration and choroidal neovascularization. Am J Ophthalmol. 1993;115:786–791
  128. Friberg TR, Musch D, PTAMD Study Group: Prophylactic treatment of age-related macular degeneration (PTAMD): update on the clinical trial. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 2904, 2002
  129. Friedlander M, Brooks PC, Shaffer RW, et al.  Definition of two angiogenic pathways by distinct αv integrins. Science. 1995;270:1500–1502
  130. Friedlander M, Theesfeld CL, Sugita M, et al.  Involvement of integrins avb3 and avb5 in ocular neovascular diseases. Proc Natl Acad Sci USA. 1996;93:9764–9769
  131. Friedman DS, Katz J, Bressler NM, et al.  Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology. 1999;106:1049–1055
  132. Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am J Ophthalmol. 1997;124:677–682
  133. Friedman E. The role of the atherosclerotic process in the pathogenesis of age-related macular degeneration. Am J Ophthalmol. 2000;130:658–663
  134. Fujii GY, Juan E, Pieramici DJ, et al.  Inferior limited macular translocation for subfoveal choroidal neovascularization secondary to age-related macular degeneration: 1-year visual outcome and recurrence report (1). Am J Ophthalmol. 2002;134:69–74
  135. Fujii GY, Pieramici DJ, Humayun MS, et al.  Complications associated with limited macular translocation. Am J Ophthalmol. 2000;130:751–762
  136. Fujiyama S, Matsubara H, Nozawa Y, et al.  Angiotensin AT(1) and AT(2) receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (EGF)-mediated EGF receptor transactivation. Circ Res. 2001;88:22–29
  137. Fukumura D, Gohongi T, Kadambi A, et al.  Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci USA. 2001;98:2604–2609
  138. Fukuzawa K, Inokami Y, Tokumura A, Terao J, Suzuki A. Rate constants for quenching singlet oxygen and activities for inhibiting lipid peroxidation of carotenoids and alpha-tocopherol in liposomes. Lipids. 1998;33:751–756
  139. Fung WE. Interferon alpha 2a for treatment of age-related macular degeneration. Am J Ophthalmol. 1991;112:349–350
  140. Fuse N, Suzuki T, Wada Y, et al.  Molecular genetic analysis of ABCR gene in Japanese dry form age-related macular degeneration. Jpn J Ophthalmol. 2000;44:245–249
  141. Gaillard ER, Atherton SJ, Eldred G, Dillon J. Photophysical studies on human retinal lipofuscin. Photochem Photobiol. 1995;61:448–453
  142. Gao G, Li Y, Zhang D, et al.  Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization. FEBS Lett. 2001;489:270–276
  143. Garrett KL, Shen WY, Rakoczy PE. In vivo use of oligonucleotides to inhibit choroidal neovascularisation in the eye. J Gene Med. 2001;3:373–383
  144. Gass JD. Drusen and disciform macular detachment and degeneration. Trans Am Ophthalmol Soc. 1972;70:409–436
  145. Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol. 1973;90:206–217
  146. Gehlbach PL, Yamamoto S, Demetriades AM, et al: Periocular adenovirus-mediated delivery of pigment epithelium-derived factor inhibits choroidal neovascularization. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 4595, 2002
  147. Gerszten RE, Garcia-Zepeda EA, Lim YC, et al.  MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398:718–723
  148. Gilbert RE, Kelly DJ, Cox AJ, et al.  Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia. 2000;43:1360–1367
  149. Glacet-Bernard A, Simon P, Hamelin N, et al.  Translocation of the macula for management of subfoveal choroidal neovascularization: comparison of results in age-related macular degeneration and degenerative myopia. Am J Ophthalmol. 2001;131:78–89
  150. Good DJ, Polverini PJ, Rastinejad F, et al.  A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA. 1990;87:6624–6628
  151. Gottfredsdottir MS, Sverrisson T, Musch DC, Stefansson E. Age related macular degeneration in monozygotic twins and their spouses in Iceland. Acta Ophthalmol Scand. 1999;77:422–425
  152. Gottsch JD, Bynoe LA, Harlan JB, et al.  Light-induced deposits in Bruch's membrane of protoporphyric mice. Arch Ophthalmol. 1993;111:126–129
  153. Gottsch JD, Pou S, Bynoe LA, Rosen GM. Hematogenous photosensitization. A mechanism for the development of age-related macular degeneration. Invest Ophthalmol Vis Sci. 1990;31:1674–1682
  154. Green WR. Histopathology of age-related macular degeneration. Mol Vis. 1999;5:27
  155. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology. 1993;100:1519–1535
  156. Green WR, Key SN. Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc. 1977;75:180–254
  157. Grossniklaus HE, Cingle KA, Yoon YD, et al.  Correlation of histologic 2-dimensional reconstruction and confocal scanning laser microscopic imaging of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol. 2000;118:625–629
  158. Grossniklaus HE, Ling JX, Wallace TM, et al.  Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis. 2002;8:119–126
  159. Grossniklaus HE, Martinez JA, Brown VB, et al.  Immunohistochemical and histochemical properties of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol. 1992;114:464–472
  160. Grunwald JE, Hariprasad SM, DuPont J. Effect of aging on foveolar choroidal circulation. Arch Ophthalmol. 1998;116:150–154
  161. Grunwald JE, Hariprasad SM, DuPont J, et al.  Foveolar choroidal blood flow in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1998;39:385–390
  162. Guerrin M, Moukadiri H, Chollet P, et al.  Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro. J Cell Physiol. 1995;164:385–394
  163. Guo L, Hussain AA, Limb GA, Marshall J. Age-dependent variation in metalloproteinase activity of isolated human Bruch's membrane and choroid. Invest Ophthalmol Vis Sci. 1999;40:2676–2682
  164. Gurne DH, Tso MO, Edward DP, Ripps H. Antiretinal antibodies in serum of patients with age-related macular degeneration. Ophthalmology. 1991;98:602–607
  165. Gutsmann-Conrad A, Heydari AR, You S, Richardson A. The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp Cell Res. 1998;241:404–413
  166. Guymer RH, Hageman GS, Bird AC. Influence of laser photocoagulation on choroidal capillary cytoarchitecture. Br J Ophthalmol. 2001;85:40–46
  167. Guymer RH, Heon E, Lotery AJ, et al.  Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. Arch Ophthalmol. 2001;119:745–751
  168. Haas A, Prettenhofer U, Stur M, et al.  Morphologic characteristics of disciform scarring after radiation treatment for age-related macular degeneration. Ophthalmology. 2000;107:1358–1363
  169. Hageman GS: Topographical differences in the structure and composition of Bruch's membrane may help explain the predilection of the macula for degeneration in age-related macular degeneration. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 1988, 2002
  170. Hageman GS, Luthert PJ, Victor Chong NH, et al.  An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the rpe-bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705–732
  171. Hageman GS, Mullins RF. Molecular composition of drusen as related to substructural phenotype. Mol Vis. 1999;5:28
  172. Hageman GS, Mullins RF, Russell SR, et al.  Vitronectin is a constituent of ocular drusen and the vitronectin gene is expressed in human retinal pigmented epithelial cells. FASEB J. 1999;13:477–484
  173. Haimovici R, Owens SL, Fitzke FW, Bird AC. Dark adaptation in age-related macular degeneration: relationship to the fellow eye. Graefes Arch Clin Exp Ophthalmol. 2002;240:90–95
  174. Hall NF, Gale CR, Syddall H, et al.  Risk of macular degeneration in users of statins: cross sectional study. Br Med J. 2001;323:375–376
  175. Hamdi HK, Reznik J, Castellon R, et al.  Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration. Biochem Biophys Res Commun. 2002;295:668–672
  176. Hammes HP, Brownlee M, Jonczyk A, et al.  Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med. 1996;2:529–533
  177. Hammes HP, Hoerauf H, Alt A, et al.  Nϵ (carboxymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1999;40:1855–1859
  178. Hammond BR, Fuld K, Curran-Celentano J. Macular pigment density in monozygotic twins. Invest Ophthalmol Vis Sci. 1995;36:2531–2541
  179. Hammond CJ, Webster AR, Snieder H, et al.  Genetic influence on early age-related maculopathy: a twin study. Ophthalmology. 2002;109:730–736
  180. Handa JT, Verzijl N, Matsunaga H, et al.  Increase in the advanced glycation end product pentosidine in Bruch's membrane with age. Invest Ophthalmol Vis Sci. 1999;40:775–779
  181. Hangai M, Moon YS, Kitaya N, et al.  Systemically expressed soluble tie2 inhibits intraocular neovascularization. Hum Gene Ther. 2001;12:1311–1321
  182. Hangai M, Murata T, Miyawaki N, et al.  Angiopoietin-1 upregulation by vascular endothelial growth factor in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2001;42:1617–1625
  183. Hanssen R. Zur anatomie der scheibenformigen degeneration der netzhaumitte. Z Augenh. 1930;72:360–368
  184. Harmey JH, Dimitriadis E, Kay E, et al.  Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998;5:271–278
  185. Hartnett ME, Weiter JJ, Garsd A, Jalkh AE. Classification of retinal pigment epithelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol. 1992;230:11–19
  186. Hartnett ME, Weiter JJ, Staurenghi G, Elsner AE. Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology. 1996;103:2042–2053
  187. Hattenbach LO, Falk B, Nurnberger F, et al.  Detection of inducible nitric oxide synthase and vascular endothelial growth factor in choroidal neovascular membranes. Ophthalmologica. 2002;216:209–214
  188. Hayes KC. Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest Ophthalmol. 1974;13:499–510
  189. Heeschen C, Jang JJ, Weis M, et al.  Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001;7:833–839
  190. Hegner CA. Retinitis exsudativa bei Lymphogranulomatosis. Klin Monatsbl Augenheil. 1916;57:27–48
  191. Heiba IM, Elston RC, Klein BE, Klein R. Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol. 1994;11:51–67
  192. Heidenkummer HP, Kampik A. Surgical extraction of subretinal pseudotumors in age related macular degeneration. Clinical, morphologic and immunohistochemical results. Ophthalmologe. 1995;92:631–639
  193. Heier JS, Greene WL, rhuFabV2 Study Group: rhuFabV2 (an anti-VEGF antibody fragment) in neovascular AMD: safety and tolerability of multiple intravitreal injections. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 2520, 2002
  194. Heuberger RA, Mares-Perlman JA, Klein R, et al.  Relationship of dietary fat to age-related maculopathy in the Third National Health and Nutrition Examination Survey. Arch Ophthalmol. 2001;119:1833–1838
  195. Hewitt AT, Nakazawa K, Newsome DA. Analysis of newly synthesized Bruch's membrane proteoglycans. Invest Ophthalmol Vis Sci. 1989;30:478–486
  196. Hikichi T, Mori F, Takamiya A, et al.  Inhibitory effect of losartan on laser-induced choroidal neovascularization in rats. Am J Ophthalmol. 2001;132:587–589
  197. Hinton DR, He S, Lopez PF. Apoptosis in surgically excised choroidal neovascular membranes in age-related macular degeneration. Arch Ophthalmol. 1998;116:203–209
  198. Hirata A, Feeney-Burns L. Autoradiographic studies of aged primate macular retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1992;33:2079–2090
  199. Ho AC, Maguire MG, Yoken J, et al.  Laser-induced drusen reduction improves visual function at 1 year. Ophthalmology. 1999;106:1367–1373
  200. Holekamp NM, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol. 2002;134:220–227
  201. Holz FG, Bellman C, Staudt S, et al.  Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;42:1051–1056
  202. Holz FG, Schutt F, Kopitz J, et al.  Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 1999;40:737–743
  203. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch Ophthalmol. 1994;112:402–406
  204. Holz FG, Wolfensberger TJ, Piguet B, et al.  Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology. 1994;101:1522–1528
  205. Holz FG, Wolfensberger TJ, Piguet B, et al.  Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology. 1994;101:1522–1528
  206. Honda M, Sakamoto T, Ishibashi T, et al.  Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration. Gene Ther. 2000;7:978–985
  207. Honda S, Farboud B, Hjelmeland LM, Handa JT. Induction of an aging mRNA retinal pigment epithelial cell phenotype by matrix-containing advanced glycation end products in vitro. Invest Ophthalmol Vis Sci. 2001;42:2419–2425
  208. Hope GM, Dawson WW, Engel HM, et al.  A primate model for age related macular drusen. Br J Ophthalmol. 1992;76:11–16
  209. Hussain AA, Starita C, Marshall J. A new drug-based strategy for intervention in age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2001;42:S223
  210. Hutchings H, Maitre-Boube M, Tombran-Tink J, Plouet J. Pigment epithelium-derived factor exerts opposite effects on endothelial cells of different phenotypes. Biochem Biophys Res Commun. 2002;294:764–769
  211. Hyman L, Schachat AP, He Q, Leske MC. Hypertension, cardiovascular disease, and age-related macular degeneration. Age-related macular degeneration risk factors study group. Arch Ophthalmol. 2000;118:351–358
  212. Hyman LG, Lilienfeld AM, Ferris FL, Fine SL. Senile macular degeneration: a case-control study. Am J Epidemiol. 1983;118:213–227
  213. Ishibashi T, Hata Y, Yoshikawa H, et al.  Expression of vascular endothelial growth factor in experimental choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol. 1997;235:159–167
  214. Ishibashi T, Murata T, Hangai M, et al.  Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol. 1998;116:1629–1632
  215. Jaffe EA, Leung LL, Nachman RL, et al.  Thrombospondin is the endogenous lectin of human platelets. Nature. 1982;295:246–248
  216. Jin GF, Hurst JS, Godley BF. Hydrogen peroxide stimulates apoptosis in cultured human retinal pigment epithelial cells. Curr Eye Res. 2001;22:165–173
  217. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res. 2001;73:887–896
  218. Johnson LV, Ozaki S, Staples MK, et al.  A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res. 2000;70:441–449
  219. Kadonosono K, Yazama F, Itoh N, et al.  Expression of matrix metalloproteinase-7 in choroidal neovascular membranes in age-related macular degeneration. Am J Ophthalmol. 1999;128:382–384
  220. Kamei M, Hollyfield JG. TIMP-3 in Bruch's membrane: changes during aging and in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1999;40:2367–2375
  221. Kamizuru H, Kimura H, Yasukawa T, et al.  Monoclonal antibody-mediated drug targeting to choroidal neovascularization in the rat. Invest Ophthalmol Vis Sci. 2001;42:2664–2672
  222. Kaplan HJ, Leibole MA, Tezel T, Ferguson TA. Fas ligand (CD95 ligand) controls angiogenesis beneath the retina. Nat Med. 1999;5:292–297
  223. Karwatowski WS, Jeffries TE, Duance VC, et al.  Preparation of Bruch's membrane and analysis of the age-related changes in the structural collagens. Br J Ophthalmol. 1995;79:944–952
  224. Kaven C, Spraul CW, Zavazava N, et al.  Thalidomide and prednisolone inhibit growth factor-induced human retinal pigment epithelium cell proliferation in vitro. Ophthalmologica. 2001;215:284–289
  225. Kayatz P, Thumann G, Luther TT, et al.  Oxidation causes melanin fluorescence. Invest Ophthalmol Vis Sci. 2001;42:241–246
  226. Keck PJ, Hauser SD, Krivi G, et al.  Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–1312
  227. Kennedy CJ, Rakoczy PE, Constable IJ. Lipofuscin of the retinal pigment epithelium: a review. Eye. 1995;9:763–771
  228. Killingsworth MC, Sarks JP, Sarks SH. Macrophages related to Bruch's membrane in age-related macular degeneration. Eye. 1990;4:613–621
  229. Kim I, Moon SO, Park SK, et al.  Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ Res. 2001;89:477–479
  230. Kimura H, Sakamoto T, Hinton DR, et al.  A new model of subretinal neovascularization in the rabbit. Invest Ophthalmol Vis Sci. 1995;36:2110–2119
  231. Kimura K, Isashiki Y, Sonoda S, et al.  Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration. Am J Ophthalmol. 2000;130:769–773
  232. Klaver CC, Kliffen M, van Duijn CM, et al.  Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet. 1998;63:200–206
  233. Klaver CC, Wolfs RC, Assink JJ, et al.  Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol. 1998;116:1646–1651
  234. Klein ML, Mauldin WM, Stoumbos VD. Heredity and age-related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol. 1994;112:932–937
  235. Klein ML, Schultz DW, Edwards A, et al.  Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol. 1998;116:1082–1088
  236. Klein R, Clegg L, Cooper LS, et al.  Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol. 1999;117:1203–1210
  237. Klein R, Klein BE, Jensen SC. The relation of cardiovascular disease and its risk factors to the 5-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;104:1804–1812
  238. Klein R, Klein BE, Jensen SC, et al.  Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2001;119:1354–1359
  239. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;104:7–21
  240. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology. 1992;99:933–943
  241. Klein R, Klein BE, Marino EK, et al.  Early age-related maculopathy in the cardiovascular health study. Ophthalmology. 2003;110:25–33
  242. Klein R, Klein BE, Moss SE. Relation of smoking to the incidence of age-related maculopathy. The Beaver Dam Eye Study. Am J Epidemiol. 1998;147:103–110
  243. Klein R, Klein BE, Tomany SC, et al.  Ten-year incidence and progression of age-related maculopathy: The Beaver Dam eye study. Ophthalmology. 2002;109:1767–1779
  244. Klein R, Klein BEK, Wong TY, et al.  The association of cataract and cataract surgery with the long-term incidence of age-related maculopathy. The Beaver Dam Eye Study. Arch Ophthalmol. 2002;120:1551–1558
  245. Kliffen M, Lutgens E, Daemen MJ, et al.  The APO(∗)E3-Leiden mouse as an animal model for basal laminar deposit. Br J Ophthalmol. 2000;84:1415–1419
  246. Kliffen M, Sharma HS, Mooy CM, et al.  Increased expression of angiogenic growth factors in age-related maculopathy. Br J Ophthalmol. 1997;81:154–162
  247. Krott R, Staar S, Muller RP, et al.  External beam radiation in patients suffering from exudative age-related macular degeneration. A matched-pairs study and 1-year clinical follow-up. Graefes Arch Clin Exp Ophthalmol. 1998;236:916–921
  248. Kruse FE, Joussen AM, Rohrschneider K, et al.  Thalidomide inhibits corneal angiogenesis induced by vascular endothelial growth factor. Graefes Arch Clin Exp Ophthalmol. 1998;236:461–466
  249. Krzystolik MG, Afshari MA, Adamis AP, et al.  Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002;120:338–346
  250. Kuhn D, Meunier I, Soubrane G, Coscas G. Imaging of chorioretinal anastomoses in vascularized retinal pigment epithelium detachments. Arch Ophthalmol. 1995;113:1392–1398
  251. Kureishi Y, Luo Z, Shiojima I, et al.  The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med. 2000;6:1004–1010
  252. Kuroki M, Voest EE, Amano S, et al.  Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest. 1996;98:1667–1675
  253. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929–1934
  254. Kvanta A, Shen WY, Sarman S, et al.  Matrix metalloproteinase (MMP) expression in experimental choroidal neovascularization. Curr Eye Res. 2000;21:684–690
  255. Kwak N, Okamoto N, Wood JM, Campochiaro PA. VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000;41:3158–3164
  256. Lafaut BA, Aisenbrey S, Vanden Broecke C, Bartz-Schmidt KU. Clinicopathological correlation of deep retinal vascular anomalous complex in age related macular degeneration. Br J Ophthalmol. 2000;84:1269–1274
  257. Lai CC, Wu WC, Chen SL, et al.  Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Invest Ophthalmol Vis Sci. 2001;42:2401–2407
  258. Lai YK, Shen WY, Brankov M, et al.  Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Ther. 2002;9:804–813
  259. Lambert V, Munaut C, Jost M, et al.  Matrix metalloproteinase-9 contributes to choroidal neovascularization. Am J Pathol. 2002;161:1247–1253
  260. Lambert V, Munaut C, Noel A, et al.  Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J. 2001;15:1021–1027
  261. Lappas A, Weinberger AW, Foerster AM, et al.  Iris pigment epithelial cell translocation in exudative age-related macular degeneration. A pilot study in patients. Graefes Arch Clin Exp Ophthalmol. 2000;238:631–641
  262. Lee PC, Kibbe MR, Schuchert MJ, et al.  Nitric oxide induces angiogenesis and upregulates αvβ3 integrin expression on endothelial cells. Microvasc Res. 2000;60:269–280
  263. Leung DW, Cachianes G, Kuang WJ, et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309
  264. Lewis H, Kaiser PK, Lewis S, Estafanous M. Macular translocation for subfoveal choroidal neovascularization in age-related macular degeneration: a prospective study. Am J Ophthalmol. 1999;128:135–146
  265. Lewis H, Straatsma BR, Foos RY. Chorioretinal juncture. Multiple extramacular drusen. Ophthalmology. 1986;93:1098–1112
  266. Li W, Yanoff M, Li Y, He Z. Artificial senescence of bovine retinal pigment epithelial cells induced by near-ultraviolet in vitro. Mech Ageing Dev. 1999;110:137–155
  267. Li ZY, Tso MO, Wang HM, Organisciak DT. Amelioration of photic injury in rat retina by ascorbic acid: a histopathologic study. Invest Ophthalmol Vis Sci. 1985;26:1589–1598
  268. Little HL, Showman JM, Brown BW. A pilot randomized controlled study on the effect of laser photocoagulation of confluent soft macular drusen. Ophthalmology. 1997;104:623–631
  269. Loffler KU, Lee WR. Basal linear deposit in the human macula. Graefes Arch Clin Exp Ophthalmol. 1986;224:493–501
  270. Lonchampt M, Pennel L, Duhault J. Hyperoxia/normoxia-driven retinal angiogenesis in mice: a role for angiotensin II. Invest Ophthalmol Vis Sci. 2001;42:429–432
  271. Lopez PF, Sippy BD, Lambert HM, et al.  Transdifferentiated retinal pigment epithelial cells are immunoreactive forvascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996;37:855–868
  272. Lu M, Kuroki M, Amano S, et al.  Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998;101:1219–1224
  273. Luna J, Tobe T, Mousa SA, et al.  Antagonists of integrin αvβ3 inhibit retinal neovascularization in a murine model. Lab Invest. 1996;75:563–573
  274. Macular Photocoagulation Study Group . Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Arch Ophthalmol. 1986;104:503–512
  275. Macular Photocoagulation Study Group . Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. 1991;109:1109–1114
  276. Macular Photocoagulation Study Group . Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol. 1994;112:500–509
  277. Macular Photocoagulation Study Group . Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol. 1994;112:480–488
  278. Macular Photocoagulation Study Group . Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol. 1997;115:741–747
  279. Maguire MG, Fine SL, Maguire AM, et al.  Results of the age-related macular degeneration and thalidomide study (AMDATS). Invest Ophthalmol Vis Sci. 2001;42:S233
  280. Maguire P, Vine AK. Geographic atrophy of the retinal pigment epithelium. Am J Ophthalmol. 1986;102:621–625
  281. Maisonpierre PC, Suri C, Jones PF, et al.  Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997;277:55–60
  282. Majji AB, Cao J, Chang KY, et al.  Age-related retinal pigment epithelium and Bruch's membrane degeneration in senescence-accelerated mouse. Invest Ophthalmol Vis Sci. 2000;41:3936–3942
  283. Majji AB, Hayashi A, Kim HC, et al.  Inhibition of choriocapillaris regeneration with genistein. Invest Ophthalmol Vis Sci. 1999;40:1477–1486
  284. Malek G, Li CM, Guidry C, et al.  Apolipoprotein B in cholesterol-containing drusen and basal deposits of human eyes with age-related maculopathy. Am J Pathol. 2003;162:413–425
  285. Mandai M, Takahashi M, Miyamoto H, et al.  Long-term outcome after radiation therapy for subfoveal choroidal neovascularization associated with age-related macular degeneration. Jpn J Ophthalmol. 2000;44:530–537
  286. Marcus DM, Maguire MG, Maguire AM, Fine SL: The age-related macular degeneration radiotherapy trial: baseline characteristics. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 1207, 2002
  287. Mares-Perlman JA, Brady WE, Klein R, et al.  Serum antioxidants and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol. 1995;113:1518–1523
  288. Mares-Perlman JA, Brady WE, Klein R, et al.  Dietary fat and age-related maculopathy. Arch Ophthalmol. 1995;113:743–748
  289. Marmorstein LY, Munier FL, Arsenijevic Y, et al.  Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci USA. 2002;99:13067–13072
  290. Matsunaga H, Handa JT, Aotaki-Keen A, et al.  β-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999;40:197–202
  291. Matsunaga H, Handa JT, Gelfman CM, Hjelmeland LM. The mRNA phenotype of a human RPE cell line at replicative senescence. Mol Vis. 1999;5:39
  292. McCarty CA, Mukesh BN, Fu CL, et al.  Risk factors for age-related maculopathy: the Visual Impairment Project. Arch Ophthalmol. 2001;119:1455–1462
  293. McFarlane S, McMullen CB, Henry DN, et al.  Advanced glycation endproducts (AGEs) modulate cathepsin D expression in retinal pigment epithelium (RPE): implications for age-related dysfunction. Invest Ophthalmol Vis Sci. 2001;42:S414
  294. McLeod DS, Taomoto M, Otsuji T, et al.  Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2002;43:1986–1993
  295. Melder RJ, Koenig GC, Witwer BP, et al.  During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med. 1996;2:992–997
  296. Meyers SM, Greene T, Gutman FA. A twin study of age-related macular degeneration. Am J Ophthalmol. 1995;120:757–766
  297. Midena E, Degli Angeli C, Blarzino MC, et al.  Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci. 1997;38:469–477
  298. Midena E, Segato T, Blarzino MC, Degli Angeli C. Macular drusen and the sensitivity of the central visual field. Doc Ophthalmol. 1994;88:179–185
  299. Miller H, Miller B, Ishibashi T, Ryan SJ. Pathogenesis of laser-induced choroidal subretinal neovascularization. Invest Ophthalmol Vis Sci. 1990;31:899–908
  300. Miller H, Miller B, Ryan SJ. Correlation of choroidal subretinal neovascularization with fluorescein angiography. Am J Ophthalmol. 1985;99:263–271
  301. Miller H, Miller B, Ryan SJ. Newly-formed subretinal vessels. Fine structure and fluorescein leakage. Invest Ophthalmol Vis Sci. 1986;27:204–213
  302. Miller H, Miller B, Ryan SJ. The role of retinal pigment epithelium in the involution of subretinal neovascularization. Invest Ophthalmol Vis Sci. 1986;27:1644–1652
  303. Miller JW, Adamis AP, Shima DT, et al.  Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994;145:574–584
  304. Mishima K, Handa JT, Aotaki-Keen A, et al.  Senescence-associated b-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci. 1999;40:1590–1593
  305. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology. 1995;102:1450–1460
  306. Mitchell P, Smith W, Wang JJ. Iris color, skin sun sensitivity, and age-related maculopathy. The Blue Mountains Eye Study. Ophthalmology. 1998;105:1359–1363
  307. Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: The Blue Mountains eye study. Ophthalmology. 2002;109:1092–1097
  308. Mitchell P, Wang JJ, Smith W, Leeder SR. Smoking and the 5-year incidence of age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 2002;120:1357–1363
  309. Miyajima-Uchida H, Hayashi H, Beppu R, et al.  Production and accumulation of thrombospondin-1 in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2000;41:561–567
  310. Miyamoto K, Khosrof S, Bursell SE, et al.  Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol. 2000;156:1733–1739
  311. Miyamoto K, Khosrof S, Bursell SE, et al.  Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci USA. 1999;96:10836–10841
  312. Monaco WA, Wormington CM. The rhesus monkey as an animal model for age-related maculopathy. Optom Vis Sci. 1990;67:532–537
  313. Moore DJ, Clover GM. The effect of age on the macro-molecular permeability of human Bruch's membrane. Invest Ophthalmol Vis Sci. 2001;42:2970–2975
  314. Moore DJ, Hussain AA, Marshall J. Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci. 1995;36:1290–1297
  315. Moravski CJ, Kelly DJ, Cooper ME, et al.  Retinal neovascularization is prevented by blockade of the renin-angiotensin system. Hypertension. 2000;36:1099–1104
  316. Mori K, Ando A, Gehlbach P, et al.  Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol. 2001;159:313–320
  317. Mori K, Duh E, Gehlbach P, et al.  Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol. 2001;188:253–263
  318. Mori K, Gehlbach P, Ando A, et al.  Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2002;43:2428–2434
  319. Mori K, Gehlbach P, Yamamoto S, et al.  AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci. 2002;43:1994–2000
  320. Moromizato Y, Stechschulte S, Miyamoto K, et al.  CD18 and ICAM-1-dependent corneal neovascularization and inflammation after limbal injury. Am J Pathol. 2000;157:1277–1281
  321. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem. 1999;74:135–143
  322. Mullins RF, Hageman GS. Histochemical comparison of ocular “drusen” in monkey and human. In:  LaVail M editors. Degenerative Retinal Diseases. New York: Plenum Press; 1997;p. 1–10
  323. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835–846
  324. Newsome DA, Swartz M, Leone NC, et al.  Oral zinc in macular degeneration. Arch Ophthalmol. 1988;106:192–198
  325. Nicolas MG, Fujiki K, Murayama K, et al.  Studies on the mechanism of early onset macular degeneration in cynomolgus (Macaca fascicularis) monkeys (I. Abnormal con-centrations of two proteins in the retina). Exp Eye Res. 1996;62:211–219
  326. Nicolas MG, Fujiki K, Murayama K, et al.  Studies on the mechanism of early onset macular degeneration in cynomolgus monkeys (II. Suppression of metallothionein synthesis in the retina in oxidative stress). Exp Eye Res. 1996;62:399–408
  327. Ninomiya Y, Lewis JM, Hasegawa T, Tano Y. Retinotomy and foveal translocation for surgical management of subfoveal choroidal neovascular membranes. Am J Ophthalmol. 1996;122:613–621
  328. Nishimura T, Goodnight R, Prendergast RA, Ryan SJ. Activated macrophages in experimental subretinal neovascularization. Ophthalmologica. 1990;200:39–44
  329. Noell WK, Walker VS, Kang BS, Berman S. Retinal damage by light in rats. Invest Ophthalmol. 1966;5:450–473
  330. Nozaki M, Ozeki H, Ogura Y. Immunolocalization of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in choroidal neovascularization of human. Invest Ophthalmol Vis Sci. 2001;42:S228
  331. Ogata N, Matsushima M, Takada Y, et al.  Expression of basic fibroblast growth factor mRNA in developing choroidal neovascularization. Curr Eye Res. 1996;15:1008–1018
  332. Ogata N, Yamamoto C, Miyashiro M, et al.  Expression of transforming growth factor-b mRNA in experimental choroidal neovascularization. Curr Eye Res. 1997;16:9–18
  333. Oh H, Takagi H, Suzuma K, et al.  Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem. 1999;274:15732–15739
  334. Oh H, Takagi H, Takagi C, et al.  The potential angiogenic role of macrophages in the formation of choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1999;40:1891–1898
  335. Ohno-Matsui K, Morita I, Tombran-Tink J, et al.  Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol. 2001;189:323–333
  336. Okamoto N, Tobe T, Hackett SF, et al.  Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol. 1997;151:281–291
  337. Okamoto T, Tanaka S, Stan AC, et al.  Advanced glycation end products induce angiogenesis in vivo. Microvasc Res. 2002;63:186–195
  338. Okubo A, Rosa RH, Bunce CV, et al.  The relationships of age changes in retinal pigment epithelium and Bruch's membrane. Invest Ophthalmol Vis Sci. 1999;40:443–449
  339. Olin KL, Morse LS, Murphy C, et al.  Trace element status and free radical defense in elderly rhesus macaques (Macaca mulatta) with macular drusen. Proc Soc Exp Biol Med. 1995;208:370–377
  340. Omenn GS, Goodman GE, Thornquist MD, et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155
  341. Organisciak DT, Darrow RM, Jiang YL, Blanks JC. Retinal light damage in rats with altered levels of rod outer segment docosahexaenoate. Invest Ophthalmol Vis Sci. 1996;37:2243–2257
  342. Organisciak DT, Wang HM, Li ZY, Tso MO. The protective effect of ascorbate in retinal light damage of rats. Invest Ophthalmol Vis Sci. 1985;26:1580–1588
  343. Otani A, Takagi H, Oh H, et al.  Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. Diabetes. 2001;50:867–875
  344. Otani A, Takagi H, Oh H, et al.  Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1999;40:1912–1920
  345. Pagenstecher H, Genth C. Atlas der Pathologischen Anatomie des Augapfels. Wiesbaden: CW Kreidel; 1875;
  346. Palm R, Strand T, Hallmans G. Zinc, total protein, and albumin in CSF of patients with cerebrovascular diseases. Acta Neurol Scand. 1986;74:308–313
  347. Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest. 1997;100:3131–3139
  348. Paul L. Choroiditis exsudativa under dem bilde der scheibenformigen entartung der netzhautmitte. Z Augenh. 1927;63:205–223
  349. Pauleikhoff D, Spital G, Radermacher M, et al.  A fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease. Arch Ophthalmol. 1999;117:1353–1358
  350. Pauleikhoff D, Zuels S, Sheraidah GS, et al.  Correlation between biochemical composition and fluorescein binding of deposits in Bruch's membrane. Ophthalmology. 1992;99:1548–1553
  351. Penfold PL, Killingsworth MC, Sarks SH. Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol. 1985;223:69–76
  352. Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res. 2001;20:385–414
  353. Penfold PL, Provis JM, Billson FA. Age-related macular degeneration: ultrastructural studies of the relationship of leucocytes to angiogenesis. Graefes Arch Clin Exp Ophthalmol. 1987;225:70–76
  354. Penfold PL, Provis JM, Furby JH, et al.  Autoantibodies to retinal astrocytes associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 1990;228:270–274
  355. Penfold PL, Wen L, Madigan MC, et al.  Triamcinolone acetonide modulates permeability and intercellular adhesion molecule-1 (ICAM-1) expression of the ECV304 cell line: implications for macular degeneration. Clin Exp Immunol. 2000;121:458–465
  356. Penn JS, Rajaratnam VS, Collier RJ, Clark AF. The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2001;42:283–290
  357. Pharmacological Therapy for Macular Degeneration Study Group . Interferon alfa-2a is ineffective for patients with choroidal neovascularization secondary to age-related macular degeneration. Results of a prospective randomized placebo-controlled clinical trial. Arch Ophthalmol. 1997;115:865–872
  358. Pieramici DJ, Bressler NM, Bressler SB, Schachat AP. Choroidal neovascularization in black patients. Arch Ophthalmol. 1994;112:1043–1046
  359. Pieramici DJ, De Juan E, Fujii GY, et al.  Limited inferior macular translocation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. Am J Ophthalmol. 2000;130:419–428
  360. Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol. 1996;114:1219–1228
  361. Plantner JJ, Jiang C, Smine A. Increase in interphotoreceptor matrix gelatinase A (MMP-2) associated with age-related macular degeneration. Exp Eye Res. 1998;67:637–645
  362. Polak BC, Baarsma GS, Snyers B. Diffuse retinal pigment epitheliopathy complicating systemic corticosteroid treatment. Br J Ophthalmol. 1995;79:922–925
  363. Pollack A, Korte GE, Heriot WJ, Henkind P. Ultrastructure of Bruch's membrane after krypton laser photocoagulation (II. Repair of Bruch's membrane and the role of macrophages). Arch Ophthalmol. 1986;104:1377–1382
  364. Potter JW, Thallemer JM. Geographic atrophy of the retinal pigment epithelium: diagnosis and vision rehabilitation. J Am Optom Assoc. 1981;52:503–508
  365. Pournaras CJ, Miller JW, Gragoudas ES, et al.  Systemic hyperoxia decreases vascular endothelial growth factor gene expression in ischemic primate retina. Arch Ophthalmol. 1997;115:1553–1558
  366. Radiation Therapy for Age-related Macular Degeneration: A prospective, randomized, double-masked trial on radiation therapy for neovascular age-related macular degeneration (RAD Study). Ophthalmology. 1999;106:2239–2247
  367. Radisavljevic Z, Avraham H, Avraham S. Vascular endothelial growth factor up-regulates ICAM-1 expression via the phosphatidylinositol 3 OH-kinase/AKT/nitric oxide pathway and modulates migration of brain microvascular endothelial cells. J Biol Chem. 2000;275:20770–20774
  368. Rakoczy PE, Lai CM, Baines M, et al.  Modulation of cathepsin D activity in retinal pigment epithelial cells. Biochem J. 1997;324:935–940
  369. Rakoczy PE, Zhang D, Robertson T, et al.  Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. Am J Pathol. 2002;161:1515–1524
  370. Ramrattan RS, van der Schaft TL, Mooy CM, et al.  Morphometric analysis of Bruch's membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci. 1994;35:2857–2864
  371. Ranson NT, Danis RP, Ciulla TA, Pratt L. Intravitreal triamcinolone in subfoveal recurrence of choroidal neovascularisation after laser treatment in macular degeneration. Br J Ophthalmol. 2002;86:527–529
  372. Rasmussen H, Chu KW, Campochiaro P, et al.  Clinical protocol. An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neo-vascular age-related macular degeneration (AMD). Hum Gene Ther. 2001;12:2029–2032
  373. Rawes V, Kipling D, Kill IR, Faragher RG. The kinetics of senescence in retinal pigmented epithelial cells: a test for the telomere hypothesis of ageing?. Biochemistry (Mosc). 1997;62:1291–1295
  374. Raz I, Karsai D, Katz M. The influence of zinc supplementation on glucose homeostasis in NIDDM. Diabetes Res. 1989;11:73–79
  375. Razavi S, Corjay MH, Thomas MA, et al.  Expression of integrins avb3 and avb5 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 2001;42:S773
  376. Reddy VM, Zamora RL, Kaplan HJ. Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1995;120:291–301
  377. Rivera A, White K, Stohr H, et al.  A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000;67:800–813
  378. Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995;108:2369–2379
  379. Robinson MR, Baffi J, Yuan P, et al.  Safety and pharmacokinetics of intravitreal 2-methoxyestradiol implants in normal rabbit and pharmacodynamics in a rat model of choroidal neovascularization. Exp Eye Res. 2002;74:309–317
  380. Rodanant N, Friberg TR, Cheng L, et al.  Predictors of drusen reduction after subthreshold infrared (810 nm) diode laser macular grid photocoagulation for nonexudative age-related macular degeneration. Am J Ophthalmol. 2002;134:577–585
  381. Rodriguez de Turco EB, Gordon WC, Bazan NG. Rapid and selective uptake, metabolism, and cellular distribution of docosahexaenoic acid among rod and cone photoreceptor cells in the frog retina. J Neurosci. 1991;11:3667–3678
  382. Rodriguez-Coleman H, Spaide RF, Yannuzzi LA. Treatment of angiomatous lesions of the retina with photodynamic therapy. Retina. 2002;22:228–232
  383. Rohan RM, Fernandez A, Udagawa T, et al.  Genetic heterogeneity of angiogenesis in mice. FASEB J. 2000;14:871–876
  384. Ross RD, Barofsky JM, Cohen G, et al.  Presumed macular choroidal watershed vascular filling, choroidal neovascularization, and systemic vascular disease in patients with age-related macular degeneration. Am J Ophthalmol. 1998;125:71–80
  385. Rozanowska M, Jarvis-Evans J, Korytowski W, et al.  Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem. 1995;270:18825–18830
  386. Rulon LL, Robertson JD, Lovell MA, et al.  Serum zinc levels and Alzheimer's disease. Biol Trace Elem Res. 2000;75:79–85
  387. Ryan SJ. Subretinal neovascularization. Natural history of an experimental model. Arch Ophthalmol. 1982;100:1804–1809
  388. Sakurai E, Taguchi H, Anand A, et al: Targeted disruption of the CD18 or ICAM-1 gene inhibits choroidal neovascularization. Invest Ophthalmol Vis Sci, In press
  389. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye. 1988;2:552–577
  390. Sarks JP, Sarks SH, Killingsworth MC. Evolution of soft drusen in age-related macular degeneration. Eye. 1994;8:269–283
  391. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol. 1976;60:324–341
  392. Sarks SH, Arnold JJ, Killingsworth MC, Sarks JP. Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study. Br J Ophthalmol. 1999;83:358–368
  393. Sarks SH, Van Driel D, Maxwell L, Killingsworth M. Softening of drusen and subretinal neovascularization. Trans Ophthalmol Soc UK. 1980;100:414–422
  394. Sarraf D, Gin T, Yu F, et al.  Long-term drusen study. Retina. 1999;19:513–519
  395. Schalch W. Carotenoids in the retina-a review of their possible role in preventing or limiting damage caused by light and oxygen. EXS. 1992;62:280–298
  396. Schatz H, McDonald HR. Atrophic macular degeneration. Rate of spread of geographic atrophy and visual loss. Ophthalmology. 1989;96:1541–1551
  397. Schaumberg DA, Christen WG, Hankinson SE, Glynn RJ. Body mass index and the incidence of visually significant age-related maculopathy in men. Arch Ophthalmol. 2001;119:1259–1265
  398. Schneider S, Greven CM, Green WR. Photocoagulation of well-defined choroidal neovascularization in age-related macular degeneration: clinicopathologic correlation. Retina. 1998;18:242–250
  399. Schoeppner G, Chuang EL, Bird AC. The risk of fellow eye visual loss with unilateral retinal pigment epithelial tears. Am J Ophthalmol. 1989;108:683–685
  400. Schutt F, Davies S, Kopitz J, et al.  Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 2000;41:2303–2308
  401. Schutt F, Ueberle B, Schnolzer M, et al.  Proteome analysis of lipofuscin in human retinal pigment epithelial cells. FEBS Lett. 2002;528:217
  402. Schwartz BS. Monocyte synthesis of thrombospondin. The role of platelets. J Biol Chem. 1989;264:7512–7517
  403. Schwesinger C, Yee C, Rohan RM, et al.  Intrachoroidal neovascularization in transgenic mice overexpressing vascular endothelial growth factor in the retinal pigment epithelium. Am J Pathol. 2001;158:1161–1172
  404. Seaber JH, Machemer R. Adaptation to monocular torsion after macular translocation. Graefes Arch Clin Exp Ophthalmol. 1997;235:76–81
  405. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol. 1997;123:199–206
  406. Seddon JM, Rosner B, Sperduto RD, et al.  Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol. 2001;119:1191–1199
  407. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. J Am Med Assoc. 1996;276:1141–1146
  408. Seigel D. AREDS investigators distort findings. Arch Ophthalmol. 2002;120:100–101
  409. Semkova I, Kreppel F, Welsandt G, et al.  Autologous transplantation of genetically modified iris pigment epithelial cells: A promising concept for the treatment of age-related macular degeneration and other disorders of the eye. Proc Natl Acad Sci USA. 2002;99:13090–13095
  410. Senger DR, Galli SJ, Dvorak AM, et al.  Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–985
  411. Sennlaub F, Courtois Y, Goureau O. Nitric oxide synthase-II is expressed in severe corneal alkali burns and inhibits neovascularization. Invest Ophthalmol Vis Sci. 1999;40:2773–2779
  412. Sennlaub F, Courtois Y, Goureau O. Inducible nitric oxide synthase mediates the change from retinal to vitreal neovascularization in ischemic retinopathy. J Clin Invest. 2001;107:717–725
  413. Shafiee A, Penn JS, Krutzsch HC, et al.  Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1. Invest Ophthalmol Vis Sci. 2000;41:2378–2388
  414. Shalinsky DR, Brekken J, Zou H, et al.  Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann N Y Acad Sci. 1999;878:236–270
  415. Shamsi FA, Boulton M. Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. Invest Ophthalmol Vis Sci. 2001;42:3041–3046
  416. Shastry BS, Trese MT. Evaluation of the peripherin/RDS gene as a candidate gene in families with age-related macular degeneration. Ophthalmologica. 1999;213:165–170
  417. Shen WY, Garrett KL, Wang CG, et al.  Preclinical evaluation of a phosphorothioate oligonucleotide in the retina of rhesus monkey. Lab Invest. 2002;82:167–182
  418. Shen WY, Yu MJ, Barry CJ, Constable IJ, Rakoczy PE. Expression of cell adhesion molecules and vascular endothelial growth factor in experimental choroidal neovascularisation in the rat. Br J Ophthalmol. 1998;82:1063–1071
  419. Sheraidah G, Steinmetz R, Maguire J, et al.  Correlation between lipids extracted from Bruch's membrane and age. Ophthalmology. 1993;100:47–51
  420. Shima DT, Adamis AP, Ferrara N, et al.  Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med. 1995;1:182–193
  421. Shima DT, Deutsch U, D'Amore PA. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett. 1995;370:203–208
  422. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843–845
  423. Singerman LJ, EyeTech Study Group: Anti-VEGF therapy for subfoveal choroidal neovascularization to age-related macular degeneration: Phase IB results. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 2908, 2002.
  424. Slakter JS, Singerman LJ, Yannuzzi LA, et al: Sub-Tenon's administration of the angiostatic agent anecortave acetate in AMD patients with subfoveal choroidal neovascularization (CNV) - the clinical outcome. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 2909, 2002.
  425. Slakter JS, Yannuzzi LA, Schneider U, et al.  Retinal choroidal anastomoses and occult choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2000;107:742–753
  426. Smiddy WE, Fine SL. Prognosis of patients with bilateral macular drusen. Ophthalmology. 1984;91:271–277
  427. Smith W, Assink J, Klein R, et al.  Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology. 2001;108:697–704
  428. Smith W, Mitchell P, Leeder SR. Smoking and age-related maculopathy. The Blue Mountains Eye Study. Arch Ophthalmol. 1996;114:1518–1523
  429. Smith W, Mitchell P, Leeder SR. Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol. 2000;118:401–404
  430. Smith W, Mitchell P, Leeder SR, Wang JJ. Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 1998;116:583–587
  431. Soubrane G, Cohen SY, Delayre T, et al.  Basic fibroblast growth factor experimentally induced choroidal angiogenesis in the minipig. Curr Eye Res. 1994;13:183–195
  432. Souied EH, Benlian P, Amouyel P, et al.  The e4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol. 1998;125:353–359
  433. Souied EH, Ducroq D, Rozet JM, et al.  ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000;41:244–247
  434. Spaide RF, Guyer DR, McCormick B, et al.  External beam radiation therapy for choroidal neovascularization. Ophthalmology. 1998;105:24–30
  435. Spandau U, Toksoy A, Holz F, Schrader W, Liesenhoff H. High expression of angiogenic chemokines in choroidal neovascularization membranes. Invest Ophthalmol Vis Sci. 2000;41:S836
  436. Sparrow CP, Burton CA, Hernandez M, et al.  Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol. 2001;21:115–121
  437. Sparrow JR, Nakanishi K, Parish CA. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 2000;41:1981–1989
  438. Sperduto RD, Hiller R. Systemic hypertension and age-related maculopathy in the Framingham Study. Arch Ophthalmol. 1986;104:216–219
  439. Spilsbury K, Garrett KL, Shen WY, et al.  Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am J Pathol. 2000;157:135–144
  440. Stangos N, Voutas S, Topouzis F, Karampatakis V. Contrast sensitivity evaluation in eyes predisposed to age-related macular degeneration and presenting normal visual acuity. Ophthalmologica. 1995;209:194–198
  441. Steen B, Sejersen S, Berglin L, et al.  Matrix metalloproteinases and metalloproteinase inhibitors in choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1998;39:2194–2200
  442. Steinmetz RL, Haimovici R, Jubb C, et al.  Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change. Br J Ophthalmol. 1993;77:549–554
  443. Stellmach VV, Crawford SE, Zhou W, Bouck N. Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci USA. 2001;98:2593–2597
  444. Stone EM, Lotery AJ, Munier FL, et al.  A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999;22:199–202
  445. Stone WL, Farnsworth CC, Dratz EA. A reinvestigation of the fatty acid content of bovine, rat and frog retinal rod outer segments. Exp Eye Res. 1979;28:387–397
  446. Submacular Surgery Trials Pilot Study Investigators . Submacular surgery trials randomized pilot trial of laser photo-coagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: (I. Ophthalmic outcomes submacular surgery trials pilot study report number 1). Am J Ophthalmol. 2000;130:387–407
  447. Submacular Surgery Trials Pilot Study Investigators . Submacular surgery trials randomized pilot trial of laser photo-coagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: (II. Quality of life outcomes submacular surgery trials pilot study report number 2). Am J Ophthalmol. 2000;130:408–418
  448. Sundelin S, Wihlmark U, Nilsson SE, Brunk UT. Lipofuscin accumulation in cultured retinal pigment epithelial cells reduces their phagocytic capacity. Curr Eye Res. 1998;17:851–857
  449. Sundelin SP, Nilsson SE. Lipofuscin-formation in retinal pigment epithelial cells is reduced by antioxidants. Free Radic Biol Med. 2001;31:217–225
  450. Sundelin SP, Nilsson SE, Brunk UT. Lipofuscin-formation in cultured retinal pigment epithelial cells is related to their melanin content. Free Radic Biol Med. 2001;30:74–81
  451. Suner IJ, Tafur CM, Espinosa-Heidmann DG, et al: Nicotine increases severity of choroidal neovascularization. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 1292, 2002.
  452. Sunness JS, Applegate CA, Gonzalez-Baron J. Improvement of visual acuity over time in patients with bilateral geographic atrophy from age-related macular degeneration. Retina. 2000;20:162–169
  453. Sunness JS, Gonzalez-Baron J, Bressler NM, et al.  The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration. Ophthalmology. 1999;106:910–919
  454. Sunness JS, Johnson MA, Massof RW, Marcus S. Retinal sensitivity over drusen and nondrusen areas. A study using fundus perimetry. Arch Ophthalmol. 1988;106:1081–1084
  455. Sunness JS, Massof RW, Johnson MA, et al.  Peripheral retinal function in age-related macular degeneration. Arch Ophthalmol. 1985;103:811–816
  456. Sunness JS, Rubin GS, Applegate CA, et al.  Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104:1677–1691
  457. Suri C, Jones PF, Patan S, et al.  Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87:1171–1180
  458. Suri C, McClain J, Thurston G, et al.  Increased vascularization in mice overexpressing angiopoietin-1. Science. 1998;282:468–471
  459. Suter M, Reme C, Grimm C, et al.  Age-related macular degeneration. The lipofuscin component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem. 2000;275:39625–39630
  460. Suzuma I, Mandai M, Takagi H, et al.  17 β-estradiol increases VEGF receptor-2 and promotes DNA synthesis in retinal microvascular endothelial cells. Invest Ophthalmol Vis Sci. 1999;40:2122–2129
  461. Suzuma K, Takagi H, Otani A, et al.  Expression of thrombospondin-1 in ischemia-induced retinal neovascularization. Am J Pathol. 1999;154:343–354
  462. Taichman NS, Young S, Cruchley AT, et al.  Human neutrophils secrete vascular endothelial growth factor. J Leukoc Biol. 1997;62:397–400
  463. Takahashi T, Nakamura T, Hayashi A, et al.  Inhibition of experimental choroidal neovascularization by overexpression of tissue inhibitor of metalloproteinases-3 in retinal pigment epithelium cells. Am J Ophthalmol. 2000;130:774–781
  464. Tanemura M, Miyamoto N, Mandai M, Honda Y. Estrogen may enhance VEGFR-2 expression in the process of laser-induced CNV formation. Invest Ophthalmol Vis Sci. 2001;42:S96
  465. Tate DJ, Miceli MV, Newsome DA. Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1995;36:1271–1279
  466. Taylor HR, Munoz B, West S, et al.  Visible light and risk of age-related macular degeneration. Trans Am Ophthalmol Soc. 1990;88:163–173
  467. Taylor HR, Tikellis G, Robman LD, et al.  Vitamin E supplementation and macular degeneration: randomised controlled trial. BMJ. 2002;325:11
  468. Thach AB, Marx JL, Frambach DA, et al.  Choroidal hypoperfusion after surgical excision of subfoveal neovascular membranes in age-related macular degeneration. Int Ophthalmol. 1996;20:205–213
  469. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group . The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035
  470. The Eye Disease Case Control Study Group . Risk factors for neovascular age-related macular degeneration. Arch Ophthalmol. 1992;110:1701–1708
  471. The Eyetech Study Group . Preclinical and Phase 1a clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina. 2002;22:143–152
  472. Thomas EL, Tressler CS, Murphy RP: Efficacy of SnET2 photodynamic therapy for choroidal neovascularization in age-related macular degeneration: Phase III pivotal trial results. Association for Research in Vision and Ophthalmology Annual Meeting, Abstract 983, 2002.
  473. Thomas MA, Dickinson JD, Melberg NS, et al.  Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology. 1994;101:1384–1396
  474. Thumann G, Aisenbrey S, Schraermeyer U, et al.  Transplantation of autologous iris pigment epithelium after removal of choroidal neovascular membranes. Arch Ophthalmol. 2000;118:1350–1355
  475. Thurston G, Suri C, Smith K, et al.  Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science. 1999;286:2511–2514
  476. Tobe T, Okamoto N, Vinores MA, et al.  Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci. 1998;39:180–188
  477. Tobe T, Ortega S, Luna JD, et al.  Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol. 1998;153:1641–1646
  478. Tolentino MJ, Miller JW, Gragoudas ES, et al.  Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103:1820–1828
  479. Tolentino MJ, Miller S, Gaudio AR, Sandberg MA. Visual field deficits in early age-related macular degeneration. Vision Res. 1994;34:409–413
  480. Tomany SC, Klein R, Klein BE. The relation of coffee and caffeine to the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Am J Ophthalmol. 2001;132:271–273
  481. Tombran-Tink J, Shivaram SM, Chader GJ, et al.  Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci. 1995;15:4992–5003
  482. Toth CA, Freedman SF. Macular translocation with 360-degree peripheral retinectomy impact of technique and surgical experience on visual outcomes. Retina. 2001;21:293–303
  483. Treatment of age related macular degeneration with photodynamic therapy (TAP) Study Group . Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials-TAP report. Arch Ophthalmol. 1999;117:1329–1345
  484. Treatment of age related macular degeneration with photodynamic therapy (TAP) Study Group . Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin—two-year results of 2 randomized clinical trials—TAP Report 2. Arch Ophthalmol. 2001;119:198–207
  485. Tripathi RC, Li J, Tripathi BJ, et al.  Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology. 1998;105:232–237
  486. Uhlmann S, Friedrichs U, Eichler W, et al.  Direct measurement of VEGF-induced nitric oxide production by choroidal endothelial cells. Microvasc Res. 2001;62:179–189
  487. Ulshafer RJ, Engel HM, Dawson WW, et al.  Macular degeneration in a community of rhesus monkeys. Ultrastructural observations. Retina. 1987;7:198–203
  488. Unemori EN, Ferrara N, Bauer EA, Amento EP. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol. 1992;153:557–562
  489. Valmaggia C, Ries G, Ballinari P. A 5-year follow-up study for distance visual acuity after low dose radiation on subfoveal choroidal neovascularization in age-related macular degeneration. Doc Ophthalmol. 2001;103:201–209
  490. van der Schaft TL, Mooy CM, de Bruijn WC, de Jong PT. Early stages of age-related macular degeneration: an immunofluorescence and electron microscopy study. Br J Ophthalmol. 1993;77:657–661
  491. van Kuijk FJ, Buck P. Fatty acid composition of the human macula and peripheral retina. Invest Ophthalmol Vis Sci. 1992;33:3493–3496
  492. van Leeuwen R, Vingerling JR, de Jong PT. Risk of macular degeneration with statin use should be interpreted with caution. BMJ. 2001;323:1308
  493. VandenLangenberg GM, Mares-Perlman JA, Klein R, et al.  Associations between antioxidant and zinc intake and the 5-year incidence of early age-related maculopathy in the Beaver Dam Eye Study. Am J Epidemiol. 1998;148:204–214
  494. Vingerling JR, Dielemans I, Bots ML, et al.  Age-related macular degeneration is associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol. 1995;142:404–409
  495. Vingerling JR, Hofman A, Grobbee DE, de Jong PT. Age-related macular degeneration and smoking. The Rotterdam Study. Arch Ophthalmol. 1996;114:1193–1196
  496. Wada M, Ogata N, Otsuji T, Uyama M. Expression of vascular endothelial growth factor and its receptor (KDR/flk-1) mRNA in experimental choroidal neovascularization. Curr Eye Res. 1999;18:203–213
  497. Wang F, Rendahl KG, Manning WC, et al.  AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat. Invest Ophthalmol Vis Sci. 2003;44:781–790
  498. Watkins ML, Erickson JD, Thun MJ, et al.  Multivitamin use and mortality in a large prospective study. Am J Epidemiol. 2000;152:149–162
  499. Watzke RC, Soldevilla JD, Trune DR. Morphometric analysis of human retinal pigment epithelium: correlation with age and location. Curr Eye Res. 1993;12:133–142
  500. Webster AR, Heon E, Lotery AJ, et al.  An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001;42:1179–1189
  501. Weeks DE, Conley YP, Tsai H, et al.  Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol. 2001;132:682–692
  502. Weiter JJ, Delori FC, Wing GL, Fitch KA. Relationship of senile macular degeneration to ocular pigmentation. Am J Ophthalmol. 1985;99:185–187
  503. West S, Vitale S, Hallfrisch J, et al.  Are antioxidants or supplements protective for age-related macular degeneration?. Arch Ophthalmol. 1994;112:222–227
  504. West SK, Rosenthal FS, Bressler NM, et al.  Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol. 1989;107:875–879
  505. Wihlmark U, Wrigstad A, Roberg K, et al.  Lipofuscin accumulation in cultured retinal pigment epithelial cells causes enhanced sensitivity to blue light irradiation. Free Radic Biol Med. 1997;22:1229–1234
  506. Wilcox DK. Vectorial accumulation of cathepsin D in retinal pigmented epithelium: effects of age. Invest Ophthalmol Vis Sci. 1988;29:1205–1212
  507. Wing GL, Blanchard GC, Weiter JJ. The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1978;17:601–607
  508. Witzenbichler B, Maisonpierre PC, Jones P, et al.  Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J Biol Chem. 1998;273:18514–18521
  509. Wood JP, Osborne NN. The influence of zinc on caspase-3 and DNA breakdown in cultured human retinal pigment epithelial cells. Arch Ophthalmol. 2001;119:81–88
  510. Wu YQ, Becerra SP. Proteolytic activity directed toward pigment epithelium-derived factor in vitreous of bovine eyes. Implications of proteolytic processing. Invest Ophthalmol Vis Sci. 1996;37:1984–1993
  511. Wu YQ, Notario V, Chader GJ, Becerra SP. Identification of pigment epithelium-derived factor in the interphotoreceptor matrix of bovine eyes. Protein Expr Purif. 1995;6:447–456
  512. Wyszynski RE, Bruner WE, Cano DB, et al.  A donor-age-dependent change in the activity of α-mannosidase in human cultured RPE cells. Invest Ophthalmol Vis Sci. 1989;30:2341–2347
  513. Yamada H, Yamada E, Hackett SF, et al.  Hyperoxia causes decreased expression of vascular endothelial growth factor and endothelial cell apoptosis in adult retina. J Cell Physiol. 1999;179:149–156
  514. Yamada H, Yamada E, Kwak N, et al.  Cell injury unmasks a latent proangiogenic phenotype in mice with increased expression of FGF2 in the retina. J Cell Physiol. 2000;185:135–142
  515. Yan SD, Schmidt AM, Anderson GM, et al.  Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994;269:9889–9897
  516. Yannuzzi LA, Negrao S, Iida T, et al.  Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001;21:416–434
  517. Yasukawa T, Kimura H, Tabata Y, et al.  Active drug targeting with immunoconjugates to choroidal neovascularization. Curr Eye Res. 2000;21:952–961
  518. Yellayi S, Naaz A, Szewczykowski MA, et al.  The phytoestrogen genistein induces thymic and immune changes: A human health concern?. Proc Natl Acad Sci USA. 2002;99:7616–7621
  519. Yi X, Ogata N, Komada M, et al.  Vascular endothelial growth factor expression in choroidal neovascularization in rats. Graefes Arch Clin Exp Ophthalmol. 1997;235:313–319
  520. Young TL, Anthony DC, Pierce E, et al.  Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. J AAPOS. 1997;1:105–110
  521. Zhang NL, Samadani EE, Frank RN. Mitogenesis and retinal pigment epithelial cell antigen expression in the rat after krypton laser photocoagulation. Invest Ophthalmol Vis Sci. 1993;34:2412–2424
  522. Zhou Y, Lee AS. Mechanism for the suppression of the mammalian stress response by genistein, an anticancer phytoestrogen from soy. J Natl Cancer Inst. 1998;90:381–388
  523. Zurdel J, Finckh U, Menzer G, et al.  CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol. 2002;86:214–219

 Supported, in part, by a Foundation Fighting Blindness Career Development Award (JA), Heed Ophthalmic Foundation (JA, BKA), AOS-Knapp Testimonial Fund (JA), University of Kentucky Physician Scientist Award (JA), Prevent Blindness America/Fight for Sight Grant-in-Aid (JA), National Eye Institute (APA), Massachusetts Lions Research Fund (APA), Falk Foundation (APA), Iaccoca Foundation (APA), and the Roberta Siegel Fund (APA). The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

PII: S0039-6257(03)00030-4

doi: 10.1016/S0039-6257(03)00030-4

Survey of Ophthalmology
Volume 48, Issue 3 , Pages 257-293 , May 2003